Packaged stable enema solution or suspension containing 5-aminosalicyclic acid

ABSTRACT

A packaged enema solution or suspension consisting essentially of an effective amount of 5-ASA or a pharmaceutically acceptable salt or ester thereof, a chelating agent, in antioxidant and a buffer, the solution or suspension having a pH value of from 4 to 7 and being contained in a plastic bottle under an inert gas, the plastic bottle being packaged in a diffusion-tight light-impervious package in the same inert gas as is present in the bottle.

This application is a continuation of application Ser. No. 529,769,filed Sept. 6, 1983, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention concerns an enema solution or suspension which issuitable for rectal administration of5-.[.aminosalicyclic.]..Iadd.aminosalicylic .Iaddend.acid (5-ASA) inmammals. The present enema solutions are useful in the treatment ofbowel diseases, in particular, ulcerative colitis, Crohn's diseaselocated in the colon and .[.proctoigmoiditis.]..Iadd.proctosigmoiditis.Iaddend..

2. State of the Prior Art

.[.Salicyclazosulfapyridine.]. .Iadd.Salicylazosulfapyridine.Iaddend.(SASP) has for a long period of time been a cornerstone in thetreatment of ulcerative colitis and has been used in variouspharmaceutical dosage forms including enemas. When SASP reaches thecolon, it is split by bacteria into sulfapyridine (SP) and 5-ASA and, asexplained in detail in copending U.S. application Ser. No. 555,533,filed Nov. 28, 1983, which is a continuation application of Ser. No.270,517, filed May 29, 1981, now abandoned, and based on InternationalApplication No. WO81/02671, both of which are incorporated by reference,most experts now hold the active moiety of SASP to be 5-ASA.

Azad Khan et al, Lancet, 1977, pp. 892-95, compared suspensions of SASP,SP and 5-ASA administered rectally and concluded that the therapeuticactive moiety was 5-ASA and that SP only acts as a carrier to ensurethat 5-ASA is not released until it has reached the colon. Stabilitytests showed that SASP and SP suspensions were stable at roomtemperature while the 5-ASA suspension showed some decay and had to bemade up in fresh batches every three months and stored in a refrigeratoruntil used.

Similar observations were made by Campieri et al, Lancet, Aug. 8, 1981,pp. 220-21, who carried out a comparison trial between 5-ASA andhydrocortisone. Since 5-ASA turned brown in solution, they addedcharcoal to the hydrocortisone as coloring agent in order to ensuredouble-blindness.

While enemas containing 5-ASA have thus proved useful in the treatmentof ulcerative colitis, their limited stability is a major problem and asolution to this problem would be of great advantage.

It has now been discovered that the desired stability can be obtained bypackaging an aqueous solution or suspension of 5-ASA or apharmaceutically acceptable salt or ester thereof being contained in aplastic bottle under an inert gas in a diffusion-tight packageimpervious to light in the same inert gas as was used in the plasticbottle.

The 5-ASA solution or suspension should further contain a chelatingagent, an antioxidant and a buffer in order to provide a pH value offrom 4 to 7.

The presence of the same inert gas on both sides of the plastic bottleprovides an equilibrium which effectively cooperates with the variousstabilizers and the diffusion-tight light-impervious package andprovides a stability of a year or more.

SUMMARY OF THE INVENTION

Hence, the invention concerns a packaged enema solution or suspensionconsisting essentially of an effective amount of 5-ASA or apharmaceutically acceptable salt or ester thereof, a chelating agent, anantioxidant and a buffer, said solution or suspension having a pH valueof from 4 to 7 and being contained in a plastic bottle under an inertgas, said plastic bottle being packaged in a diffusion-tightlight-impervious package in the same inert gas as is present in thebottle.

BRIEF DESCRIPTION OF THE DRAWING

The invention will be further illustrated with reference to theaccompanying single FIGURE of drawing which shows a partly torn awaypackage containing a liquid-filled enema bottle.

The drawing shows a laminated foil package 1 enclosing an anema bottle 2containing an enema solution or suspension 3.

The laminated foil package 1 is heat-sealed along each edge at 1a andalong the bottom at 1b and the top at 1c, respectively.

Preferably, the package is formed from a heat-sealable plastic-metallaminate, e.g., a polyethylenealuminum laminate 4.

The bottle is constituted by a container part 6, an intermediate part 7and a sealed closure part 8.

DETAILED DESCRIPTION OF THE INVENTION

The therapeutically active ingredient 5-ASA may be present in the formof the free acid or a pharmaceutically acceptable salt or ester thereof.

The salts of 5-ASA may be acid addition salts, in particular, thehydrochloride, but any pharmaceutically acceptable, non-toxic organic orinorganic acid may be used.

Also, salts formed with the carboxylic acid group may be used. Asexamples may be mentioned alkali metal salts (K, Na), alkaline earthmetal salts (Ca, Mg), but again any pharmaceutically acceptable,non-toxic salt may be used. The Na- and Ca- salts are preferred.

In German Offenlegungsschrift No. 2,712,934, a number of esters ofortho-, meta- and .[.para-salicyclic.]. .Iadd.para-salicylic.Iaddend.acid are disclosed. Said esters are effective as ultravioletray screening compounds thereby rendering themselves useful inpreventing solar burning. The disclosed meta- (or5-).[.aminosalicyclic.]..Iadd.aminosalicylic .Iaddend.esters and anumber of related esters are also applicable in the enema according tothe invention.

Applicable esters are, e.g., straight chain or branched C₁ -C₁₈ alkylesters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl,hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, andstearyl, etc.; straight chain or branched C₂ -C₁₈ alkenyl esters, e.g.,vinyl, allyl, undecenyl, oleyl, linolenyl, etc.; C₃ -C₈ cycloalkylesters, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl, etc.; aryl esters, e.g., phenyl, toluyl,xylyl, naphthyl, etc.; alicyclic esters, e.g., menthyl, etc.; or aralkylesters, e.g., benzyl, phenethyl, etc.

Generaly speaking, the proper selection of the active ingredient dependson the selected type of formulation, the disease pattern, especially thesite and type of the disease, and the desired release of the activeingredient, as shall be further expounded below together with theconcept "effective amount".

The physical state and solubility characteristics of the 5-ASAderivatives must be taken into account when selecting a suitable carriercomposition for the ingredient.

The preferred active ingredient at present is the free acid, 5-ASA.

Preferably, the 5-ASA is extremely pure in order to preventautooxidation. The purity is manifested by the absence of additionalhigh pressure liquid chromatography (HPLC) peaks (both determinedfluospectrophotometrically and spectrophotometrically in general).

The effective amount of the 5-ASA or ester or salt thereof contained inthe enema depends upon the extent of the disease and for adultsgenerally in amounts of from 0.2 to 4 g 5-ASA per 100 ml enema will beused. Whether or not the enema- is a suspension or solution i.a. dependson the amount of 5-ASA and the pH. The solubility of 5-ASA in water isabout 2 g/100 ml at pH 7, but only about 0.2 g/100 ml at pH 4.8.

By administering an enema suspension, which might be provided at themore acidic pH values in the range from 4 to 7, a kind of slow-releaseof the 5-ASA might be obtained.

Since 5-ASA is assumed to be topically effective at the ulcer sites incase of colitis such slow release is believed to be the most beneficialto the patient.

The enema solution or suspension also contains a chelating agent toavoid autooxidation catalyzed by metal ions which may be present even inanalytic grade chemicals. Any of the classic chelating agents may beused, but the preferred chelating agents are polymethylenediaminetetraacetic acid, in particular, ethylene diaminetetraacetic acid(EDTA) and its alkali metal salts. The preferred amount of chelatingagent is from 5 to 30 mg/100 ml solution or suspension, preferably about20 mg/100 ml.

Further, the solution or suspension contains an antioxidant to preventoxidation of the 5-ASA. Preferred antioxidants are sodium or potassiumpyrosulfite, but other well-known antioxidants might be used, e.g.,ascorbic acid. The preferred amount is 50-200 mg/100 ml suspension orsolution, preferably about 100 mg/100 ml.

Further, the enema solution contains a suitable buffer in order tomaintain the desired pH value in the range of from 4 to 7. The preferredpH is from 4.5 to 5, in particular, about 4.8. This pH is advantageouslyestablished by means of a citric acid buffer since citric, acid has apka of 4.77.

Other applicable buffers are bicarbonate buffers if a pH of 6 to 7 isdesired since the pka for bicarbonate is 6.5.

Generally speaking, any buffer system might be used which provides theproper pH and does not interfere with the other components of enema.

The gas used in the bottle and the package should be inert with relationto the solution or suspension. Preferred inert gases are nitrogen orargon, but also carbon dioxide may be used if the solution or suspensioncontains a bicarbonate buffer.

The plastic bottle is preferably made by blow forming from apolyethylene granulate which has been deoxidized by alternating vacuumand nitrogen treatments.

The diffusion-tight light-impervious package material is preferably madefrom a heat-sealable plastic-metal laminate, e.g., plastic-aluminumlaminate, where any heat-sealable plastic material, e.g., polyethylene,might be used.

DESCRIPTION OF THE PREFERRED EMBODIMENT

A packaged suspension according to the invention may be prepared asfollows:

1. Preparation of a 5-ASA suspension

    ______________________________________                                        5-ASA*         1 g/100 ml                                                     EDTA           20 mg                                                          Sodium pyrosulfite                                                                           0.2 g                                                          Citric acid    1 g                                                            Sodium hydroxide                                                                             q.s. (up to pH = 4.8 about 0.35 g)                             Sterile water  up to 100 ml                                                   ______________________________________                                         *5-ASA is extremely pure to avoid autooxidiation  no additional HPLC peak     (both fluospectrophotometrically and spectrophometrically in general).   

The suspension is prepared and dispensed in an inert gas, e.g., nitrogenor argon.

2. Filling of 5-ASA suspension in a plastic bottle

The polyethylene granulate is deoxidized by alternating vacuum andnitrogen treatments. The deoxidized granulate is extruded, formed byblowing and the 5-ASA suspension is filled into a plastic bottleblower/packing machine. The inert gas used for dispensing alsoconstitutes the supporting air, blowing air and the air in the chamberin which the filling and forming procedures are taking place.

The bottle is conveyed directly to a packing chamber containing the sameinert gas in which the bottles are packed in aroma-tight,light-impervious (plastics aluminum laminate) bags which are sealed bywelding before they drop into the atmosphere.

Enema suspensions contain 1 g and 2 g 5-ASA per 100 ml prepared inanalogy with the above procedure have been tested for stability byfluospectrophotometry and HPLC.

After storage at room temperature for more than a year, no significantchange was observed neither with regard to color or 5-ASA content.

It is also to be understood that the following claims are intended tocover all of the generic and specific features of the invention hereindescribed, and all statements of the scope of the invention which, as amatter of language, might be said to fall therebetween.

What is claimed is:
 1. A packaged enema solution or suspensionconsisting essentially of an effective amount of 5-ASA or apharmaceutically acceptable salt or ester thereof, a chelating agent, anantioxidant and a buffer, said solution or suspension having a pH valueof about 4.8 and being contained in a plastic bottle under an inert gas,said plastic bottle being packaged in a diffusion-tight light-imperviouspackage in the same inert gas as is present in the bottle.
 2. A packagedenema solution or suspension according to claim 1, wherein the chelatingagent comprises EDTA, the antioxidant comprises sodium pyrosulfite andthe buffer comprises citric acid and sodium hydroxide. .[.3. A packagedenema solution or suspension according to claim 1, wherein the buffer issodium bicarbonate and hydrochloric acid..].
 4. An enema solution orsuspension according to claim 1, wherein the .[.5-aminosalicyclic.]..Iadd.5-aminosalicylic .Iaddend.acid is sufficiently pure to avoidautooxidation, having no additional HPLC fluospectrophotometric andspectrophotometric peaks.
 5. A packaged enema solution or suspensionaccording to claim 1, wherein the inert gas is argon, nitrogen or carbondioxide.
 6. A packaged enema solution or suspension according to claim 1consisting essentially of substantially pure .[.5-aminosalicyclic.]..Iadd.5-aminosalicylic .Iaddend.acid or a pharmaceutically acceptablesalt or ester thereof, ethylenediaminetetraacetic acid, sodiumpyrosulfite, citric acid, sodium hydroxide and purified water.
 7. Apackaged enema solution or suspension according to claim 1, wherein theplastic bottle is polyethylene.
 8. A packaged enema solution orsuspension according to claim 7, wherein a polyethylene granulate usedfor producing the polyethylene bottle is deoxidized by alternatelyevacuating the granulate and flooding the granulate with nitrogen gas.9. A package enema solution or suspension according to claim 8, whereinthe deoxidized granulate is extruded, formed into a bottle by means ofan inert gas, and the bottle is filled with said enema solution.
 10. Apackage enema solution or suspension according to claim 9, the filledbottle is conveyed directly to a packing chamber wherein the bottle ispacked into an aroma-tight bag under an inert gas, said bag being sealedby welding before being contacted with air.
 11. A packaged enemasolution or suspension according to claim 10, wherein the aroma-tightbag is a plastic aluminum laminate.
 12. A packaged enema solution orsuspension according to claim 11, containing per 100 ml of solutionabout 0.2 to 4.0 g .[.5-aminosalicyclic.]. .Iadd.5-aminosalicylic.Iaddend.acid, about 50 mg to 200 mg of sodium pyrosulfite, about 0.5 to1.5 g citric acid, about 0.5 to 2 g sodium hydroxide, about 5 to 30 mgsodium EDTA, and purified water.
 13. A packaged enema solution orsuspension according to claim 12, containing per 100 ml of solutionabout 1 g of .[.5-aminosalicyclic.]. .Iadd.5-aminosalicylic.Iaddend.acid, about 200 mg of sodium pyrosulfite, about 1 g citricacid, about 20 mg sodium EDTA, and sufficient sodium hydroxide andpurified water to maintain said pH of 4.8. .Iadd.14. A packaged enemasolution or suspension consisting essentially of an effective amount of5-ASA or a pharmaceutically acceptable salt or ester thereof, achelating agent, an antioxidant and a buffer, said solution orsuspension having a pH value of from 4 to 5 and being contained in aplastic bottle under an inert gas, said plastic bottle being packaged ina diffusion-tight light-impervious package in the same inert gas as ispresent in the bottle. .Iaddend. .Iadd.15. A packaged enema solution orsuspension according to claim 14, wherein the antioxidant is sodium orpotassium pyrosulfite. .Iaddend. .Iadd.16. A packaged enema solution orsuspension according to claim 15, wherein the pyrosulfite is potassiumpyrosulfite. .Iaddend. .Iadd.17. A packaged enema solution or suspensionaccording to claim 16, containing per 100 ml of solution or suspensionabout 50 mg to 200 mg of potassium pyrosulfite. .Iaddend. .Iadd.18. Apackaged enema solution or suspension according to claim 17, wherein thechelating agent is ethylene diaminetetraacetic acid or one of its alkalimetal salts. .Iaddend. .Iadd.19. A packaged enema solution or suspensionaccording to claim 18, wherein the chelating agent is one of the alkalimetal salts of ethylene diaminetetraacetic acid. .Iaddend. .Iadd.20. Apackaged enema solution or suspension according to claim 19, wherein theenema solution or suspension has a pH value of from 4.5 to
 5. .Iaddend..Iadd.21. A packaged enema solution or suspension according to claim 20,wherein the enema solution or suspension is a suspension. .Iaddend..Iadd.22. A packaged enema solution or suspension consisting essentiallyof an effective amount of 5-ASA, an alkali metal salt of ethylenediaminetetraacetic acid, potassium pyrosulfite, and a buffer, saidsolution or suspension having a pH value of from 4 to 5 and beingcontained in a plastic bottle under an inert gas, said plastic bottlebeing packaged in a diffusion-tight light-impervious package in the sameinert gas as is present in the bottle. .Iaddend. .Iadd.23. A packagedenema solution or suspension according to claim 22, wherein the enemasolution or suspension has a pH value of from 4.5 to
 5. .Iaddend..Iadd.24. A packaged enema solution or suspension according to claim 22,wherein the enema solution or suspension has a pH value of about 4.8..Iaddend. .Iadd.25. A packaged enema solution or suspension according toclaim 22, containing per 100 ml of said solution or suspension about 50mg to 200 mg of potassium pyrosulfite. .Iaddend. .Iadd.26. A packagedenema solution or suspension according to claim 25, wherein the enemasolution or suspension is a suspension. .Iaddend.